title: Adoptive regulatory T-cell therapy preserves systemic immune homeostasis after cerebral ischemia.
abstract: OBJECTIVE
  Cerebral ischemia has been shown to result in peripheral inflammatory responses followed by long-lasting immunosuppression. Our recent study demonstrated that intravenous delivery of regulatory T cells (Tregs) markedly protected against transient cerebral ischemia by suppressing neutrophil-derived matrix metallopeptidase 9 production in the periphery. However, the effect of Tregs on systemic inflammatory responses and immune status has not been fully characterized.
  
  
  METHODS
  Cerebral ischemia was induced by middle cerebral artery occlusion for 60 minutes in mice or 120 minutes in rats. Tregs were isolated from donor animals by CD4 and CD25 double selection and transferred intravenously to ischemic recipients at 2 hours after middle cerebral artery occlusion. Animals were euthanized on different days after reperfusion. The effects of Tregs on systemic inflammation and immune status were evaluated using flow cytometry, ELISAs, and immunohistochemistry.
  
  
  RESULTS
  Systemic administration of purified Tregs raises functional Tregs in the blood and peripheral organs, including spleen and lymph nodes. These exogenous Tregs remain in the blood and peripheral organs for ≥12 days. Functionally, Treg adoptive transfer markedly inhibits middle cerebral artery occlusion-induced elevation of inflammatory cytokines (interleukin-6 and tumor necrosis factor α) in the blood. Furthermore, Treg treatment corrects long-term lymphopenia and improves cellular immune functions after ischemic brain injury. As a result, Treg-treated animals exhibit decreased bacterial loads in the blood during recovery from cerebral ischemic attack.
  
  
  CONCLUSIONS
  Treg treatment did not exacerbate poststroke immunosuppression. On the contrary, Treg-treated animals displayed improved immune status after focal cerebral ischemia.
authors.affiliation: From the Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine, Pittsburgh, PA (P.L., L.M., J.C., X.H.); Anesthesiology Department of Huashan Hospital, State Key Laboratory of Medical Neurobiology and Institute of Brain Sciences, Fudan University, Shanghai, China (P.L., L.M., J.C., X.H.); Department of Neurology and Key Laboratory of Cerebral Microcirculation, University of Shandong, Taian, Shandong, China (G.Z., B.-L.S.); Affiliated Hospital of Taishan Medical College, Taian, Shandong, China (G.Z., B.-L.S.); Division of Pharmaceutical Sciences, Mylan School of Pharmacy, Duquesne University, Pittsburgh, PA (R.K.L.); and Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA (J.C., X.H.).
authors.forename: Peiying
authors.initials: P
authors.lastname: Li
authors.forename: Leilei
authors.initials: L
authors.lastname: Mao
authors.forename: Guoqing
authors.initials: G
authors.lastname: Zhou
authors.forename: Rehana K
authors.initials: RK
authors.lastname: Leak
authors.forename: Bao-Liang
authors.initials: BL
authors.lastname: Sun
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Hu
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002545:Brain Ischemia / Q000276:immunology / Q000628:therapy*; D004195:Disease Models, Animal; D006706:Homeostasis / Q000276:immunology*; D007107:Immune System / Q000276:immunology*; D051379:Mice; D051381:Rats; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000637:transplantation*
keywords: T-lymphocytes, regulatory; immunosuppression; inflammation; stroke